The present invention relates to an inclusion complex comprising Rifampicin and cyclodextrin useful as drug in tuberculosis. The present invention also relates to synthesis of Rifampicin-cyclodextrin inclusion complexes, which find use in tuberculosis therapy as drug delivery systems.
Rifampicin is an international nonproprietary name. Other names used are Rifamycin AMP, Rifampin and Rifaldazine. Rifampicin is designated by IUPAC rules as 2,7-(epoxy pentadeca[1,11,13]trienimino)naphtho[2,1-b]furan1,11(2H)-dione5,6,9,17,19,21-hexa hydroxy-23-methoxy-2,4,12,16,18,20,22-hepta methyl-8-[N-(4-methyl-1-piperazinyl)formimidoyl]-21-acetate. Rifampicin is a commonly used anti-mycobacterial drug for the treatment of tuberculosis. The chemical structure of Rifampicin is shown in FIG. 2.
Cyclodextrins (CDs) are cyclic oligosaccharides possessing hydrophobic cavities. CDs can be used in combination with various drugs either for complexation or as auxiliaries such as diluents, solubilizers or tablet ingredients (Comprehensive Supramolecular Chemistry, Vol 3, Szejtli J, Osa T, Pergamon, UK, 1996). The advantage of using CDs mainly comes from their inclusion complex formation. The complexation can protect the molecule and can eventually have considerable pharmaceutical potential.
There are various advantages for drug delivery using inclusion complex formation. Incompatible drugs can be mixed when one of them is complexed with CDs. The release rate of drugs can be controlled. The solubility of water insoluble drugs can be improved. The instability of drugs in water and the acidic environment of the stomach conditions can be improved, since the rate of hydrolysis, photo-decomposition, auto-catalytic reactions etc., are considerably reduced. Furthermore, percutaneous or rectal absorption can be improved by the enhanced release of drugs from ointments or suppository bases. Thus, CD inclusion complexes of drugs have several advantages.
The inclusion complex formation can be characterized by powder X-ray diffraction patterns and IR spectroscopy (Comprehensive Supramolecular Chemistry, Vol 3, Szejtli J, Osa T, Pergamon, UK, 1996).
A recent publication has reported the impaired bioavailability of Rifampicin in the presence of Isoniazid, an antimycobacterial drug also used in treatment of tuberculosis, in fixed dose combinations (FDCs) due to the decomposition of Rifampicin in the stomach (Chronicle Pharmabiz, p. 28, Dec. 20, 2001). The acidic environment of the stomach causes Rifampicin to be hydrolyzed to an insoluble, less absorbable form. Thus, there is a need for a formulation that protects Rifampicin from degradation in the acidic environment of the stomach.
The present invention contemplates a Rifampicin and β-cyclodextrin containing inclusion complex that may be used in the treatment of tuberculosis. This formulation is also potentially advantageous since stability and release can be controlled. Combinations of Rifampicin and cyclodextrin formulations reported so far are only dispersions of Rifampicin and cyclodextrin (East. Pharm., p. 133, vol. 41(492), 1998), that have not been isolated and characterized inclusion complexes containing Rifampicin and cyclodextrin.
Accordingly, studies were undertaken to make the inclusion complexes of Rifampicin with β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD).